Bicyclic and tricyclic heteroaromatic compounds

ABSTRACT

Disclosed are compounds of the formula: 
                         
and the pharmaceutically acceptable salts thereof, wherein W, Q, X, X 1 , Y and Z are as defined herein. These compounds bind with high selectivity and/or high affinity to the benzodiazepine site of GABA A  receptors and are therefore useful in the treatment of central nervous system (CNS) diseases and as probes for the localization of GABA A  receptors in tissue samples. Also disclosed are intermediates useful in the preparation of these compounds.

This application is a continuation application of U.S. Ser. No.10/352,519, filed Jan. 28, 2003, now U.S. Pat. No. 7,053,093; which is acontinuation application of U.S. Ser. No. 09/709,887, filed Nov. 10,2000, now U.S. Pat. No. 6,511,987; which claims the benefit of U.S. Ser.No. 60/165,054, filed Nov. 12, 1999.

FIELD OF THE INVENTION

This invention relates to heterocyclic derivatives that bind to thebenzodiazepine site of GABA_(A) receptors. This invention also relatesto pharmaceutical compositions comprising such compounds and to the useof such compounds in the treatment of central nervous system (CNS)diseases. This invention also relates to the use of these heterocycliccompounds in combination with one or more other CNS agents to potentiatethe effects of the other CNS agents. Additionally this invention relatesto the use such compounds as probes for the localization of GABA_(A)receptors in tissue sections.

BACKGROUND

The GABA_(A) receptor superfamily represents one of the classes ofreceptors through which the major inhibitory neurotransmitter,γ-aminobutyric acid, or GABA, acts. Widely, although unequally,distributed through the mammalian brain, GABA mediates many of itsactions through a complex of proteins called the GABA_(A) receptor,which causes alteration in chloride conductance and membranepolarization.

A number of cDNAs for GABA_(A) receptor subunits have beencharacterized. To date at least 6α, 3β, 3γ, 1ε, 1δ and 2ρ subunits havebeen identified. It is generally accepted that native GABA_(A) receptorsare typically composed of 2α, 2β, and 1γ subunits (Pritchett & SeeburgScience 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998;6:1-18). Evidence such as message distribution, genome localization andbiochemical study results suggest that the major naturally occurringreceptor combinations are α₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂ (Mohler et.al. Neuroch. Res. 1995; 20(5): 631-636).

Benzodiazepines exert their pharmacological actions by interacting withthe benzodiazepine binding sites associated with the GABA_(A) receptor.In addition to the benzodiazepine site, the GABA_(A) receptor containssites of interaction for several other classes of drugs. These include asteroid binding site, a picrotoxin site, and the barbiturate site. Thebenzodiazepine site of the GABA_(A) receptor is a distinct site on thereceptor complex that does not overlap with the site of interaction forGABA or for other classes of drugs that bind to the receptor (see, e.g.,Cooper, et al., The Biochemical Basis of Neuropharmacology, 6^(th) ed.,1991, pp. 145-148, Oxford University Press, New York). Earlyelectrophysiological studies indicated that a major action of thebenzodiazepines was enhancement of GABAergic inhibition. Compounds thatselectively bind to the benzodiazepine site and enhance the ability ofGABA to open GABA_(A) receptor channels are agonists of GABA receptors.Other compounds that interact with the same site but negatively modulatethe action of GABA are called inverse agonists. Compounds belonging to athird class bind selectively to the benzodiazepine site and yet havelittle or no effect on GABA activity, but can block the action ofGABA_(A) receptor agonists or inverse agonists that act at this site.These compounds are referred to as antagonists.

The important allosteric modulatory effects of drugs acting at thebenzodiazepine site were recognized early and the distribution ofactivities at different receptor subtypes has been an area of intensepharmacological discovery. Agonists that act at the benzodiazepine siteare known to exhibit anxiolytic, sedative, and hypnotic effects, whilecompounds that act as inverse agonists at this site elicit anxiogenic,cognition enhancing, and proconvulsant effects. While benzodiazepineshave a long history of pharmaceutical use as anxiolytics, thesecompounds often exhibit a number of unwanted side effects. These mayinclude cognitive impairment, sedation, ataxia, potentiation of ethanoleffects, and a tendency for tolerance and drug dependence.

GABA_(A) selective ligands may also act to potentiate the effects ofother CNS active compounds. For example, there is evidence thatselective serotonin reuptake inhibitors (SSRIs) may show greaterantidepressant activity when used in combination with GABA_(A) selectiveligands than when used alone.

SUMMARY OF THE INVENTION

This invention provides heterocyclic derivatives, particularlyimidazoquinoline and 1,2,4-triazoloquinoline derivatives, that bind tothe benzodiazepine site of the GABA_(A) receptor, including humanGABA_(A) receptors. Preferably, these compounds also bind with highaffinity to such receptors. More preferably, these compounds bind withhigh selectivity to such receptors.

The invention provides compounds of Formula I (shown below), andpharmaceutical compositions comprising compounds of Formula 1.

The invention further provides methods of treating patients sufferingfrom CNS disorders with a therapeutically effective amount of a compoundof the invention. The patient may be a human or other mammal. Treatmentof humans, domesticated companion animals (pets) and livestock animalssuffering from CNS disorders with a therapeutically effective amount ofa compound of the invention is contemplated by the invention.

In a separate aspect, the invention provides a method of potentiatingthe actions of other CNS active compounds. This method comprisesadministering a therapeutically effective amount of a compound of theinvention with another CNS active compound.

Additionally this invention provides for the use of the compounds of theinvention as probes for the localization of GABA_(A) receptors in tissuesamples, in particular, tissue sections.

The invention also provides intermediate compounds that are useful inthe preparation of compounds of Formula 1.

A broad aspect of the invention is directed to compounds of Formula 1:

And the pharmaceutically acceptable salts thereof, wherein:

-   X represents N or CR₁, wherein    -   R₁ is hydrogen, halogen, hydroxy, cyano, nitro, amino, C₁-C₆        alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono or        di(C₁-C₆)alkylamino, or amino (C₁-C₆)alkyl;-   X₁ represents N, CH, or C₁-C₆alkyl;-   Y and Z are independently hydrogen, halogen, hydroxy, cyano, nitro,    amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy,    mono or di(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl; or-   Y and Z together form an arylene ring or a C₃-C₈ cycloalkylene ring,    each of which is optionally substituted with up to four groups R₂    independently chosen at each occurrence from halogen, hydroxy,    cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,    trifluoromethoxy, mono or di(C₁-C₆)alkylamino, and    amino(C₁-C₆)alkyl;-   W is aryl or heteroaryl, each of which is optionally substituted    with one or more groups R_(A), wherein each R_(A) is independently    -   i) halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkoxy,        trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),        —SO₂N(C₁₋₈ alkyl) (C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈        alkyl) (C₁₋₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈        alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈        alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl),        —SO(C₁-C₈ alkyl), or —SO₂(C₁-C₈ alkyl);    -   ii) aryl or heteroaryl, each of which is optionally substituted        with one or two groups independently selected from halogen,        hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy,        trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino,        and amino(C₁-C₆)alkyl;    -   iii) C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl,        C₃-C₈cycloalkyl(C₁-C₃ alkyl), C₃-C₈cycloalkenyl, each of which        is unsubstituted or substituted by one or more substituents        independently selected from hydroxy, oxo, halogen, C₁-C₆alkoxy,        —CONH₂, —CONHC₁-C₆ alkyl, —CON(C₁-C₆ alkyl) (C₁-C₆ alkyl),        —COOH, and —CO₂C₁-C₆ alkyl; or    -   iv) NR₄R₅, wherein R₄, R₅ and the nitrogen to which they are        attached form a monocyclic or bicyclic ring optionally        containing one or more of oxo, O, S, SO, SO₂, or NR₆ wherein R₆        is hydrogen, C₁-C₆ alkyl, or Ar—(C₁-C₆ alkyl) where        -   Ar is aryl or heteroaryl, each of which is optionally            substituted by one or two groups independently selected from            halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl,            C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, mono or            di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl; and-   Q is selected Formulas III, IV and V:

-   -   wherein:    -   J is N or C₁-C₈ alkylene; and    -   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl, or Ar₁,        wherein Ar₁ is aryl or heteroaryl, each of which may be        substituted with one or two of R_(B), where each R_(B)        independently carries the definition of R_(A); or    -   R₉, R₁₀ and the atom to which they are attached form a 4- to        8-membered monocyclic or bicyclic ring optionally containing one        or more double bonds or one or more of oxo, O, S, SO, SO₂, or        N—R₈ wherein R₈ is hydrogen, C₁-C₈ alkyl, or Ar₁—(C₁-C₈ alkyl);        wherein Ar₁ is optionally substituted with one or two of R_(B),        where each R_(B) independently carries the definition of R_(A);        and wherein the monocyclic or bicyclic ring is optionally        substituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl;    -   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl        (C₁-C₆)alkanoyl; and    -   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, and C₁-C₈ alkoxy; or    -   R₁₁ and R₁₂ together with the atoms to which they are attached        form a 5-8 membered monocyclic ring which is optionally        substituted with one or more of halogen, hydroxy, cyano, nitro,        amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,        trifluoromethoxy, mono or di(C₁-C₆)alkylamino, or amino (C₁-C₆)        alkyl; and    -   n is 1, 2, 3, or 4; and    -   W′        -   (i) independently carries the same definition as W;        -   (ii) represents —OR where R is C₁-C₈ alkyl or            aryl(C₁-C₆)alkyl; or        -   (iii) is M₅ where M₅ is hydroxy, C₁-C₈ alkyl,            aryl(C₁-C₆)alkyl or —N(C₁-C₄ alkyl) (C₁-C₄ alkoxy).

DETAILED DESCRIPTION OF THE INVENTION

For compounds of Formula I (above) preferred aryl and heteroaryl groupsrepresenting the variable W include, but are not limited to the groupsW₁ defined as follows:

W₁: phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,indolyl, pyrazolyl or benzopyrazolyl, each of which is optionallysubstituted by one or more groups independently chosen at eachoccurrence from

-   -   halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkoxy,        trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),        —SO₂N(C₁₋₈ alkyl) (C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈        alkyl) (C₁₋₈ alkyl), —N(C₁-C₈ alkyl) CO(C₁-C₈ alkyl), —N(C₁-C₈        alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈        alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl),        —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl), and phenyl.

Especially preferred groups representing the variable W includes thegroups W₂, wherein

W₂ represents phenyl, naphthyl, thienyl, benzothienyl, pyridyl,quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,indolyl, pyrazolyl or benzopyrazolyl, each of which is optionallysubstituted by one or more groups independently chosen at eachoccurrence from

-   -   halogen, hydroxy, cyano, nitro, amino, C₁-C₆alkoxy,        trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),        —SO₂N(C₁₋₈ alkyl) (C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈        alkyl) (C₁₋₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈        alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈        alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl),        —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl), and phenyl.

A preferred arylene ring formed by Y and Z is benzo. Particularlypreferred benzo rings are unsubstituted or substituted with one, two, orthree, more preferably one or two, of R₂ where each R₂ is the same as ordifferent than every other R₂. Preferred benzo substituents are halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₆ alkyl),and —N(C₁-C₆ alkyl)₂. Highly preferred benzo substituents are halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, —NH(C₁-C₆ alkyl), and—N(C₁-C₆ alkyl)₂.

Preferred cycloalkylene rings formed by Y and Z are 5-, 6-, and7-membered cycloalkylene rings. Particularly preferred are 5-, 6-, and7-membered cycloalkylene rings are that are unsubstituted or aresubstituted with one, two, or three, preferably one or two, of R₂ whereeach R₂ is the same as or different than every other R₂. Preferredcycloalkylene substituents are halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆alkoxy, —NO₂, —CN, —SO₂NH₂, amino, —NH(C₁-C₆ alkyl), and —N(C₁-C₆alkyl)₂. Highly preferred cycloalkylene substituents are halogen,hydroxy, C₁-C₆ alkyl, C₁-C₆ alkoxy, amino, —NH(C₁-C₆ alkyl), and—N(C₁-C₆ alkyl)₂.

A preferred group of compounds of the invention includes thoserepresented by Formula A-3

wherein R₂, Q, X₁, X and W are as defined for Formula I and R₂ isindependently chosen at each occurrence.

Preferred compounds of Formula A-3 include compounds where

-   W is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,    pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl, furanyl,    benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl,    isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl,    indolyl, pyrazolyl or benzopyrazolyl, each of which is unsubstituted    or substituted with one or more substituents independently selected    from the group consisting of:    -   halogen, hydroxy, cyano, nitro, amino, C₁-C₈ alkyl, C₁-C₆alkoxy,        trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),        —SO₂N(C₁-C₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈        alkyl)(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈        alkyl)CO₂(C₁-C₈ alkyl), —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈        alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl),        —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.

Even more preferred compounds of Formula A-3 include those where

-   R₂ is independently chosen at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   Q is selected from the group consisting of Formulas III, IV and V:

-   -   wherein:    -   J is N or C₁-C₈ alkylene; and    -   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or    -   R₉, R₁₀ and the atom to which they are attached form a 4- to        8-membered monocyclic or bicyclic ring, which may contain one or        more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈        wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or        bicyclic ring is optionally substituted with C₁-C₆ alkyl or        hydroxy (C₁-C₆)alkyl;    -   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl        (C₁-C₆)alkanoyl; and    -   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, and C₁-C₈ alkoxy; or    -   R₁₁ and R₁₂ together with the atoms to which they are attached        form a 5-8 membered monocyclic ring, which is optionally        substituted with C₁-C₆ alkyl; and    -   n is 1, 2, 3, or 4;

-   W′ phenyl, pyridyl, or naphthyl; and

-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

Other preferred compounds of Formula A-3 include compounds where X₁ isCR₁ and R₁ is hydrogen or C₁-C₆ alkyl.

Preferred compounds of Formula A-3 also include compounds wherein X₁ isCR₁ and R₁ is hydrogen or C₁-C₆ alkyl, and W has the definition of W₁ ormore preferably W has the definition of W₂.

Also preferred are compounds of Formula A-3 wherein X₁ is CR₁ and R₁ ishydrogen or C₁-C₆ alkyl;

-   R₂ is independently selected at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   Q is selected from the group consisting of Formulas III, IV and V    -   wherein:    -   J is N or C₁-C₈ alkylene; and    -   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or    -   R₉, R₁₀ and the atom to which they are attached form a 4- to        8-membered monocyclic or bicyclic ring, which may contain one or        more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈        wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or        bicyclic ring is optionally substituted with C₁-C₆ alkyl or        hydroxy (C₁-C₆)alkyl;    -   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl        (C₁-C₆)alkanoyl; and    -   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, and C₁-C₈ alkoxy; or    -   R₁₁ and R₁₂ together with the atoms to which they are attached        form a 5-8 membered monocyclic ring, which is optionally        substituted with C₁-C₆ alkyl; and    -   n is 1, 2, 3, or 4;-   W′ phenyl, pyridyl, or naphthyl; and-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

Preferred W groups of Formula A-3 are those carrying k-2 substituentswhere k is the number of hydrogen atoms on the aryl or heteroaryl groupdefined by W. More preferably, the W groups carry k-3 substituents. Themost preferred W groups are those carrying 1 or 2 substituents, andthose substituents are most preferably hydroxy, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- ordi(C₁-C₆)alkylamino.

Another preferred group of compounds of the invention are those depictedby Formula A-6

wherein R₂, Q, and X are defined as in Formula I, R₂ is independentlydefined at each occurrence, and W is W₁.

More preferred are compounds of Formula A-6 are those where R₂, Q, and Xare defined as in Formula I, and W is W₂.

More preferred are compounds of Formula A-6 include those where

-   R₂ are independently selected at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   Q is selected from the group consisting of Formulas III, IV and V:

-   -   wherein:    -   J is N or C₁-C₈ alkylene; and    -   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or    -   R₉, R₁₀ and the atom to which they are attached form a 4- to        8-membered monocyclic or bicyclic ring, which may contain one or        more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈        wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or        bicyclic ring is optionally substituted with C₁-C₆ alkyl or        hydroxy C₁-C₆)alkyl;    -   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and        aryl(C₁-C₆)alkanoyl; and    -   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, and C₁-C₈ alkoxy; or    -   R₁₁ and R₁₂ together with the atoms to which they are attached        form a 5-8 membered monocyclic ring, which is optionally        substituted with C₁-C₆ alkyl; and    -   n is 1, 2, 3, or 4;

-   W′ phenyl, pyridyl, or naphthyl; and

-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

Preferred W groups of Formula A-6 are those carrying k-2 substituentswhere k is the number of hydrogen atoms on the aryl or heteroaryl groupdefined by W. More preferably, the W groups carry k-3 substituents. Themost preferred W groups are those carrying 1 or 2 substituents, andthose substituents are most preferably hydroxy, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- ordi(C₁-C₆)alkylamino.

Another preferred group of compounds of the invention is represented byFormula A-9, i.e., compound where both X and X₁ are both CH,

wherein R₁, R₂, and Q are as defined as in Formula 1, and W is W₁.

More preferred are compounds of Formula A-9 include those wherein R₂ andQ are as defined in Formula I, and W is W₁.

Most preferred compounds of formula A-9 are those wherein

-   R₂ is independently selected at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   Q is selected from the group consisting of Formulas III, IV and V:

-   -   J is N or C₁-C₈ alkylene; and    -   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or    -   R₉, R₁₀ and the atom to which they are attached form a 4- to        8-membered monocyclic or bicyclic ring, which may contain one or        more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈        wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or        bicyclic ring is optionally substituted with C₁-C₆ alkyl or        hydroxy (C₁-C₆)alkyl;    -   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl        (C₁-C₆)alkanoyl; and    -   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈        alkyl, and C₁-C₈ alkoxy; or    -   R₁₁ and R₁₂ together with the atoms to which they are attached        form a 5-8 membered monocyclic ring, which is optionally        substituted with C₁-C₆ alkyl; and    -   n is 1, 2, 3, or 4;

-   W′ phenyl, pyridyl, or naphthyl; and

-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

Preferred W groups of Formula A-9 are those carrying k-2 substituentswhere k is the number of hydrogen atoms on the aryl or heteroaryl groupdefined by W. More preferably, the W groups carry k-3 substituents. Themost preferred W groups are those carrying 1 or 2 substituents, andthose substituents are most preferably hydroxy, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, amino or mono- ordi(C₁-C₆) alkylamino.

Still another preferred group of compounds is represented by FormulaA-12.

wherein

wherein R₁, Q, and X are as defined in Formula I and

-   -   p is 1, 2, 3, and 4; and W is W₁.

More preferred compounds of Formula A-12 are those where

-   R₂, Q, and X are as defined in Formula 1;-   p is 1, 2, 3, or 4; and-   W is W₂.

Even more preferred compounds of Formula 12 are those wherein

-   R₂ is selected from the group consisting of C₁-C₆ alkyl, C₁-C₆    alkoxy, halogen, hydroxy, trifluoromethyl and trifluoromethoxy;-   Q is selected from the group consisting of Formulas III, IV and V:

wherein:

-   J is N or C₁-C₈ alkylene; and-   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or-   R₉, R₁₀ and the atom to which they are attached form a 4- to    8-membered monocyclic or bicyclic ring, which may contain one or    more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈    wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or    bicyclic ring is optionally substituted with C₁-C₆ alkyl or    hydroxy(C₁-C₆)alkyl;-   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    C₁-C₆ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and-   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    and C₁-C₈ alkoxy; or-   R₁₁ and R₁₂ together with the atoms to which they are attached form    a 5-8 membered monocyclic ring, which is optionally substituted with    C₁-C₆ alkyl; and-   n is 1, 2, 3, or 4;-   W′ phenyl, pyridyl, or naphthyl; and-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

Preferred compounds of the invention are also encompassed by FormulaA-15

-   -   wherein R₁, Q, and X are as defined in Formula 1; p is 1, 2, 3,        or 4; and W is W₁.        More compounds of Formula A-15 are those wherein    -   R₂, Q, and X are as defined in Formula 1;    -   p is 1, 2, or 3; and    -   W is W₂.

Even more preferred compounds of Formula A-15 are those where

-   R₂ is independently selected at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   Q is selected from the group consisting of Formulas III, IV and V:

wherein:

-   J is N or C₁-C₈ alkylene; and-   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or-   R₉, R₁₀ and the atom to which they are attached form a 4- to    8-membered monocyclic or bicyclic ring, which may contain one or    more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈    wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or    bicyclic ring is optionally substituted with C₁-C₆ alkyl or    hydroxy(C₁-C₆)alkyl;-   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and-   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    and C₁-C₈ alkoxy; or-   R₁₁ and R₁₂ together with the atoms to which they are attached form    a 5-8 membered monocyclic ring, which is optionally substituted with    C₁-C₆ alkyl; and-   n is 1, 2, 3, or 4;-   W′ phenyl, pyridyl, or naphthyl; and-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, c₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

Preferred compounds of the invention are also encompassed by FormulaA-17, i.e., compounds where Y and Z are not joined to form an aryl ring.

wherein X, X₁, and Q are defined as in Formula I, and W is W₁; and

-   Y and Z are independently selected from hydrogen, halogen, hydroxy,    cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,    trifluoromethoxy, mono or di(C₁-C₆)alkylamino, amino (C₁-C₆)alkyl.

More preferred compounds of Formula A-1.7 are those wherein

-   X, X₁, and Q are defined as in Formula I, and W is W₂; and-   Y and Z are independently selected from hydrogen, halogen, hydroxy,    cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,    trifluoromethoxy, mono or di(C₁-C₆)alkylamino, amino (C₁-C₆)alkyl.

Even more preferred are compounds of Formula A-17 wherein

-   X is N or CH; and-   Q is selected from the group consisting of Formulas III, IV and V:

wherein:

-   J is N or C₁-C₈ alkylene; and-   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or-   R₉, R₁₀ and the atom to which they are attached form a 4- to    8-membered monocyclic or bicyclic ring, which may contain one or    more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈    wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or    bicyclic ring is optionally substituted with C₁-C₆ alkyl or    hydroxy(C₁-C₆)alkyl;-   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆)alkanoyl; and-   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    and C₁-C₈ alkoxy; or-   R₁₁ and R₁₂ together with the atoms to which they are attached form    a 5-8 membered monocyclic ring, which is optionally substituted with    C₁-C₆ alkyl; and-   n is 1, 2, 3, or 4;-   W′ phenyl, pyridyl, or naphthyl; and-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

Other preferred compounds are represented by Formula A-18

-   W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which    is optionally substituted with one, two, or three of V₁, V₂ and V₃,    where V₁, V₂, and V₃ independently represent    -   halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino,        —NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl) (C₁-C₆ alkyl);-   R₁ and R₂ independently represent hydrogen, halogen, hydroxy, C₁-C₆    alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈    alkyl)(C₁-C₈ alkyl);-   X is nitrogen or CR₁₁₁, where R₁₁₁ is hydrogen, halogen, hydroxy,    C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or    —N(C₁-C₈ alkyl) (C₁-C₈ alkyl); and-   R₉ and R₁₀ are independently hydrogen or C₁-C₈ alkyl; or-   NR₉R₁₀ represents a 5- to 7-membered ring optionally containing one    or two double bonds, O and/or N—R₈ where R₈ is hydrogen, C₁-C₈    alkyl, or HAr—(C₁-C₈)alkyl, where HAr is phenyl, pyridinyl, or    pyrimidinyl, each of which is optionally substituted with one or two    halogen, hydroxy, hydroxy(C₁-C₆)alkyl, C₁-C₆ alkyl, C₁-C₈ alkoxy,    —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl) (C₁-C₈    alkyl).

More preferred compounds of Formula A-18 include those where X isnitrogen.

Still other more preferred compounds of Formula A-18 are those where Xis CH or a carbon atom substituted with (C₁-C₆) alkyl.

Other preferred compounds are represented by Formula A-19

-   W is phenyl, isoxazolyl, thienyl, pyridyl, quinolyl, each of which    is optionally substituted with one, two, or three of V₁, V₂ and V₃,    where V₁, V₂, and V₃ independently represent    -   halogen, hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino,        —NH(C₁-C₈ alkyl), or —N(C₁-C₈ alkyl) (C₁-C₈ alkyl);-   R₁ and R₂ independently represent hydrogen, halogen, hydroxy, C₁-C₆    alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or —N(C₁-C₈    alkyl) (C₁-C₈ alkyl);-   X is nitrogen or CR₁₁₁, where R₁₁₁ is hydrogen, halogen, hydroxy,    C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈ alkyl), or    —N(C₁-C₈ alkyl) (C₁-C₈ alkyl); and-   W′ represents    -   (i) phenyl optionally substituted with one, two, or three of T₁,        T₂ and T₃, where T₁, T₂, and T₃ independently represent halogen,        hydroxy, C₁-C₆ alkyl, C₁-C₈ alkoxy, —NO₂, —CN, amino, —NH(C₁-C₈        alkyl), or —N(C₁-C₈ alkyl) (C₁-C₈ alkyl);    -   (ii) —OR where R is C₁-C₈ alkyl or aryl(C₁-C₆)alkyl; or    -   (iii) M₅ where M₅ is hydroxy, C₁-C₈ alkyl, aryl(C₁-C₆)alkyl or        —N(C₁-C₄ alkyl) (C₁-C₄ alkoxy).

More preferred compounds of Formula A-19 include those where X isnitrogen.

Still other more preferred compounds of Formula A-19 are those where Xis CH or a carbon atom substituted with (C₁-C₆) alkyl.

Still other preferred compounds are represented by Formula A-20

-   -   wherein and Q are as defined in Formula I, and W is W₁; and        Y and Z are independently selected from hydrogen, halogen,        hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy,        trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino,        amino (C₁-C₆)alkyl.

Especially preferred definitiona of Y and Z for Formula A-20, arehydrogen, halogen, and C₁-C₆alkyl. More preferred compounds of FormulaA-20, are those where W is W₂.

Particularly preferred compounds of Formula A-20 are those wherein

-   Y and Z are independently chosen from hydrogen, halogen, and C₁-C₆    alkyl, W is W₂; and-   Q is selected from the group consisting of Formulas III, IV and V:

wherein:

-   J is N or C₁-C₈ alkylene; and-   R₉ and R₁₀ are independently hydrogen, C₁-C₈ alkyl; or-   R₉, R₁₀ and the atom to which they are attached form a 4- to    8-membered monocyclic or bicyclic ring, which may contain one or    more double bonds or one or more of oxo, O, S, SO, SO₂, or N—R₈    wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic or    bicyclic ring is optionally substituted with C₁-C₆ alkyl or    hydroxy(C₁-C₆)alkyl;-   R₁₁ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, and aryl(C₁-C₆) alkanoyl; and-   R₁₂ is selected from the group consisting of hydrogen, C₁-C₈ alkyl,    and C₁-C₈ alkoxy; or-   R₁₁ and R₁₂ together with the atoms to which they are attached form    a 5-8 membered monocyclic ring, which is optionally substituted with    C₁-C₆ alkyl; and-   n is 1, 2, 3, or 4;-   W′ phenyl, pyridyl, or naphthyl; and-   W is phenyl, thienyl, isoxazolyl, or pyridyl, each of which is    unsubstituted or substituted with one or more substituents    independently selected from the group consisting of halogen, C₁-C₆    alkyl, C₁-C₆ alkoxy, trifluoromethyl, trifluoromethoxy, and hydroxy.

For Formulas III, IV, and V

Preferred R₈ substituents on the hetero nitrogen (which is sometimepresent in the 4- to 8-membered monocyclic or bicyclic ring formed by R₉and R₁₀) are methyl, ethyl, n-propyl and isopropyl.

Preferred JR₉R₁₀ groups include 1-piperidinyl optionally mono- ordisubstituted with C₁-C₆ alkyl, preferably methyl or ethyl;1-piperazinyl optionally mono- or disubstituted with C₁-C₆ alkyl,preferably methyl or ethyl; and morpholinyl optionally mono- ordisubstituted with C₁-C₆ alkyl, preferably methyl or ethyl. Otherpreferred JR₉R₁₀ groups include pyrrolyl and imidazolinyl, each of whichis optionally mono- or disubstituted with C₁-C₃ alkyl or hydroxy (C₁-C₆)alkyl, and preferably monosubstituted with methyl, ethyl, orhydroxymethyl.

Where the nature of the substituents permits, the groups represented byJR₉R₁₀ encompass various stereoisomers. While the invention encompassesracemic mixtures and mixtures of enantiomers in which one enantiomer ispresent in an enantiomeric excess, the preferred compounds of theinvention are those where only a single, at least relatively pure,stereoisomer is present. Examples of preferred JR₉R₁₀ stereoisomersinclude the following:

As used herein, monocyclic and bicyclic rings include both carbocyclicrings where J is, e.g., CH, and, for those rings formed by NR₄R₅ andNR₉R₁₀, nitrogen-containing carbocyclic ring systems of the type havingat least one nitrogen, e.g., the nitrogen in NR₄R₅. Thus, in NR₄R₅ andNR₉R₁₀, the R₄R₅ and R₉R₁₀ groups together represent, for example, aC₄-C₆ straight chain alkylene group which together with the nitrogenatom to which, e.g., R₉ and R₁₀ are attached form a 5- to 7-memberedring system. This ring system may be further substituted with, e.g.,C₁-C₆ alkyl or may contain one or two double bonds, O, and/or asubstituted nitrogen as defined herein. In situations where J is, forexample, CH, the resulting ring can contain hetero atoms such as oxygenor nitrogen giving rise to, e.g., a 4-piperidinyl group.

When J is a C₁-C₈ alkylene group, that group is attached at one terminusto the parent carbonyl and the groups R₉ and R₁₀ are attached at anyposition along the alkylene chain. For example, JR₉R₁₀ represents groupssuch as neopentyl, t-butyl, isopropyl, 2-ethylhexyl and n-octyl.Further, R₉R₁₀ may represent an alkylene group, e.g., a C₅ alkylenegroup attached to the terminus of J where is n-propyl giving rise to acyclohexylpropyl group.

Particularly preferred compounds of Formulas A-3, A-6, and A-9, A-12,A-15, A-17, and A-20 are those where Q represents either Formula III orFormula IV. In highly preferred embodiments, Q represents Formula IIIwhere

R₉, R₁₀ and the nitrogen atom to which they are attached represent mono-or di(C₁-C₆)alkylamino; or

R₉, R₁₀ and the nitrogen to which they are attached form a 5- or6-membered ring.

The 5- and 6-membered rings are optionally substituted with C₁-C₆ alkylor hydroxy(C₁-C₆)alkyl, preferably hydroxymethyl, and optionally containone hetero atom selected from oxygen, sulfur, or nitrogen. The heterosulfur atom may be oxidized to a sulfone or sulfoxide. The heteronitrogen is optionally substituted with R₈ where R₈ represents hydrogenor C₁-C₈ alkyl.

Other particularly preferred compounds of the invention are those whereW represents optionally substituted phenyl, isoxazolyl, or thienyl.Highly preferred compounds are those where the phenyl is unsubstitutedor substituted with one or two of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,trifluoromethyl, trifluoromethoxy, or hydroxy. Other highly preferredcompounds are those where W is isoxazolyl optionally substituted withC₁-C₆ alkyl, most preferably methyl, C₁-C₆ alkoxy, or halogen. The mostpreferred compounds are those where W is phenyl optionally substitutedwith one halogen, preferably chloro or fluoro, or one hydroxy. Even morepreferably, the halogen or hydroxy group is in the ortho or paraposition of the phenyl ring.

The invention also provides intermediates of Formula A-69

wherein Y, Z, and X₁ are defined as for Formula I, R is C₁-C₆ alkyl, andR_(N) is hydrogen, C₁-C₆ alkyl, or —C(O)w where W is as defined forFormula I.

Preferred intermediate compounds can be represented by Formula A-70

wherein X₁ and R₂ are as defined for Formula I, and R and R_(N) are asdefined in Formula A-69.

Another preferred class of intermediates is represented by Formula A-71

wherein X₁, Y, and Z are defined as in Formula I, R is C₁-C-₆ alkyl and

-   W is phenyl, pyridyl, isoxazolyl, or thienyl, each of which is    unsubstituted or substituted with one or more of halogen, hydroxy,    cyano, nitro, amino, C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl,    trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)    (C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl) (C₁₋₈ alkyl),    —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),    —CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl) (C₁-C₈ alkyl),    —CO₂(C₁-C₈ alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈    alkyl) and phenyl.

More preferred are intermediate compounds of Formula A-72

wherein X₁ and R₂ are as defined in Formula I, R is C₁-C₆ alkyl, and Wrepresents W₂.

Even more preferred are intermediates of Formula A-73 wherein

-   R₂, is independently selected at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   W is W₂; and-   X₁ is N or CH.

Another group of intermediate compounds useful in preparing compounds ofthe instant invention are those of Formula A-74

wherein Y, Z, X₁, and W are as defined for Formula I, and R is C₁-C₆alkyl.

More preferred intermediate compounds are represented by formula A-75

wherein X and R₂ are as defined in Formula I, R₂ is independently chosenat each occurrence, W is W₂, and R is C₁-C₆ alkyl.

Even more preferred are intermediates of Formula A-75 wherein

-   R₂ is independently selected at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   W is W₂; and-   X is N or CR₁; wherein R₁ is selected from the group consisting of    hydrogen, halogen, hydroxy, C₁-C₆ alkyl, and C₁-C₆ alkoxy.

Still another group of intermediates that are useful in preparingcompounds of the instant invention are those of Formula A-76

wherein Y, Z, X, X₁, and W are as defined for Formula I, and M₅ ishydroxy, C₁-C₈alkyl, aryl(C₁-C₆)alkyl, or —N(C₁-C₄ alkyl) (C₁-C₄alkoxy).

A more preferred group of intermediates of Formula A-76 are those ofFormula A-77

wherein X₁, R₂ and M₅ are as defined in claim 76; and

-   W is W₂.

A preferred group of intermediates of Formula A-77 are those wherein

-   R₂ is independently selected at each occurrence from the group    consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, hydroxy,    trifluoromethyl and trifluoromethoxy;-   W is W₂; and-   X₁ is N or CH.

This invention relates to imidazoquinoline and triazoloquinolinederivatives and related compounds, preferred examples of which bind withhigh affinity to the benzodiazepine site of GABA_(A) receptors,including human GABA_(A) receptors. Preferred fused aryl substitutedtetrahydroindazoles and related compounds that bind with highselectivity to the benzodiazepine site of GABA_(A) receptors, includinghuman GABA_(A) receptors, are also included in this invention. Withoutwishing to be bound to any particular theory, it is believed that theinteraction of the compounds of Formula I with the benzodiazepine siteresults in the pharmaceutical utility of these compounds.

The invention further comprises methods of treating patients in need ofsuch treatment with an amount of a compound of the invention sufficientto alter the symptoms of a CNS disorder. Compounds of the inventionsthat act as agonists at ₂β₃γ₂ and ₃β₃γ₂ receptor subtypes are useful intreating anxiety disorders such as panic disorder, obsessive compulsivedisorder and generalized anxiety disorder; stress disorders includingpost-traumatic stress, and acute stress disorders. Compounds of theinventions that act as agonists at ₂β₃γ₂ and ₃β₃β₂ receptor subtypes arealso useful in treating depressive or bipolar disorders and in treatingsleep disorders. Compounds of the invention that act as inverse agonistsat the ₅β₃γ₂ receptor subtype or ₁β₂γ₂ and ₅β₃γ₂ receptor subtypes areuseful in treating cognitive disorders including those resulting fromDown Syndrome, neurodegenerative diseases such as Alzheimer's diseaseand Parkinson's disease, and stroke related dementia. Compounds of theinvention that act as agonists at the ₁β₂γ₂ receptor subtype are usefulin treating convulsive disorders such as epilepsy. Compounds that act asantagonists at the benzodiazepine site are useful in reversing theeffect of benzodiazepine overdose and in treating drug and alcoholaddiction.

The diseases and/or disorders that can also be treated using compoundsand compositions according to the invention include:

Depression, e.g. depression, atypical depression, bipolar disorder,depressed phase of bipolar disorder.

Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panicdisorder +/− agoraphobia, social phobia, specific phobia, Post traumaticstress disorder, obsessive compulsive disorder (OCD), dysthymia,adjustment disorders with disturbance of mood and anxiety, separationanxiety disorder, anticipatory anxiety acute stress disorder, adjustmentdisorders, cyclothymia.Sleep disorders, e.g. sleep disorders including primary insomnia,circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, includingnightmare disorder, sleep terror disorder, sleep disorders secondary todepression and/or anxiety or other mental disorders, substance inducedsleep disorder.Cognition Impairment, e.g. cognition impairment, Alzheimer's disease,Parkinson's disease, mild cognitive impairment (MCI), age-relatedcognitive decline (ARCD), stroke, traumatic brain injury, AIDSassociated dementia, and dementia associated with depression, anxiety orpsychosis.Attention Deficit Disorder, e.g. attention deficit disorder (ADD), andattention deficit and hyperactivity disorder (ADHD).

The invention also provides pharmaceutical compositions comprisingcompounds of the invention, including packaged pharmaceuticalcompositions for treating disorders responsive to GABA_(A) receptormodulation, e.g., treatment of anxiety, depression, sleep disorders orcognitive impairment by GABA_(A) receptor modulation. The packagedpharmaceutical compositions include a container holding atherapeutically effective amount of at least one GABA_(A) receptormodulator as described supra and instructions (e.g., labeling)indicating the contained GABA_(A) receptor ligand is to be used fortreating a disorder responsive to GABA_(A) receptor modulation in thepatient.

In a separate aspect, the invention provides a method of potentiatingthe actions of other CNS active compounds, which comprises administeringan effective amount of a compound of the invention in combination withanother CNS active compound. Such CNS active compounds include, but arenot limited to the following: for anxiety, serotonin receptor (e.g.5-HT_(1A)) agonists and antagonists; for anxiety and depression,neurokinin receptor antagonists or corticotropin releasing factorreceptor (CRF₁) antagonists; for sleep disorders, melatonin receptoragonists; and for neurodegenerative disorders, such as Alzheimer'sdementia, nicotinic agonists, muscarinic agents, acetylcholinesteraseinhibitors and dopamine receptor agonists. Particularly the inventionprovides a method of potentiating the antidepressant activity ofselective serotonin reuptake inhibitors (SSRIs) by administering aneffective amount of a GABA agonist compound of the invention incombination with an SSRI.

Combination administration can be carried out in a fashion analogous tothat disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3)211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le,et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, thediscussion of the use of the GABA_(A) receptor ligand3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with nicotinicagonists, muscarinic agonists, and acetylcholinesterase inhibitors, inPCT International publications Nos. WO 99/47142, WO 99/47171, and WO99/47131, respectively. Also see in this regard PCT Internationalpublication No. WO 99/37303 for its discussion of the use of a class ofGABA_(A) receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, incombination with SSRIs.

The present invention also pertains to methods of inhibiting the bindingof benzodiazepine compounds, such as Ro15-1788, to the GABA_(A)receptors which methods involve contacting a compound of the inventionwith cells expressing GABA_(A) receptors, wherein the compound ispresent at a concentration sufficient to inhibit benzodiazepine bindingto GABA_(A) receptors in vitro. This method includes inhibiting thebinding of benzodiazepine compounds to GABA_(A) receptors in vivo, e.g.,in a patient given an amount of a compound of Formula I that would besufficient to inhibit the binding of benzodiazepine compounds toGABA_(A) receptors in vitro. In one embodiment, such methods are usefulin treating benzodiazepine drug overdose. The amount of a compound thatwould be sufficient to inhibit the binding of a benzodiazepine compoundto the GABA_(A) receptor may be readily determined via an GABA_(A)receptor binding assay, such as the assay described in Example 50. TheGABA_(A) receptors used to determine in vitro binding may be obtainedfrom a variety of sources, for example from preparations of rat cortexor from cells expressing cloned human GABA_(A) receptors.

The present invention also pertains to methods for altering thesignal-transducing activity, particularly the chloride ion conductanceof GABA_(A) receptors, said method comprising exposing cells expressingsuch receptors to an effective amount of a compound of the invention.This method includes altering the signal-transducing activity ofGABA_(A) receptors in vivo, e.g., in a patient given an amount of acompound of Formula I that would be sufficient to alter thesignal-transducing activity of GABA_(A) receptors in vitro. The amountof a compound that would be sufficient to alter the signal-transducingactivity of GABA_(A) receptors may be determined via a GABA_(A) receptorsignal transduction assay, such as the assay described in Example 51.

The GABA_(A) receptor ligands provided by this invention and labeledderivatives thereof are also useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind to theGABA_(A) receptor.

Labeled derivatives the GABA_(A) receptor ligands provided by thisinvention are also useful as radiotracers for positron emissiontomography (PET) imaging or for single photon emission computerizedtomography (SPECT).

Definitions

If the compounds of the present invention have asymmetric centers, thenthis invention includes all of the optical isomers and mixtures thereof.

In addition, compounds with carbon-carbon double bonds may occur in Z-and E-forms, with all isomeric forms of the compounds being included inthe present invention.

Compounds of Formula I may contain one or more asymmetric carbon atoms,so that the compounds can exist in different stereoisomeric forms. Thesecompounds can be present as, for example, racemic mixtures, mixtures ofdiastereomers, and optically active forms including mixtures having onestereoisomer in enantiomeric excess and essentially pure stereoisomers,i.e., individual stereoisomers. In these latter situations, the singleenantiomers can be obtained by asymmetric synthesis or by resolution ofthe racemates. Resolution of the racemates can be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralHPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table Iand their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutically acceptable salts include, but are not limitedto salts of inorganic acids such as hydrochloric, sulfuric, phosphoric,diphosphoric, hydrobromic, and nitric or salts of organic acids such asformic, citric, malonic, maleic, fumaric, tartaric, succinic, acetic,lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic,salicylic and stearic. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

When any variable (e.g. C₁-C₆ alkyl, C₁-C₈ alkyl, R₁-R₈, W, X, Ar, G orQ) occurs more than one time in any formula herein, its definition oneach occurrence is independent of its definition at every otheroccurrence.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Alkyl groups may be straight, orbranched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl,butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl,and the like. Where the number of carbon atoms in the alkyl group isunspecified, the group is a C₁-C₆ alkyl groups.

The term “alkoxy” represents an alkyl group of indicated number ofcarbon atoms attached to the parent molecular moiety through an oxygenbridge. Examples of alkoxy groups include, for example, methoxy, ethoxy,propoxy and isopropoxy. Where the number of carbon atoms in the alkoxygroup is unspecified the group is C₁-C₆ alkoxy.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings. Examples of aryl groups include, for example, phenyl,naphthyl, anthryl, phenanthryl, 1,2,3,4-tetrahydronaphthyl and biphenyl.Preferred examples of aryl groups include phenyl and naphthyl.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, andiodine. Preferred halo groups are fluoro, chloro, and bromo. Mostpreferred are fluoro and chloro.

The term “heterocycloalkyl” refers to a non-aromatic ring systemcontaining at least one heteroatom selected from nitrogen, oxygen, andsulfur. The heterocycloalkyl ring may be optionally fused to orotherwise attached to other heterocycloalkyl rings and/or non-aromatichydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7members. Examples of heterocycloalkyl groups include, for example,piperazine, morpholine, piperidine, tetrahydrofuran, pyrrolidine, andpyrazole. Preferred heterocycloalkyl groups include piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,1-thiomorpholinyl, andpyrolidinyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom selected from nitrogen, oxygen, and sulfur. Theheteroaryl ring may be fused or otherwise attached to one or moreheteroaryl rings, aromatic or non-aromatic hydrocarbon rings orheterocycloalkyl rings. Examples of heteroaryl groups include, forexample, pyridine, furan, thiophene, 5,6,7,8-tetrahydroisoquinoline andpyrimidine. Preferred examples of heteroaryl groups include thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl,tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.

The term “hydroxyalkyl” as used herein, refers to a hydroxy group,attached to the parent molecular moiety through an alkyl group, asdefined above.

As used herein, the term “oxo” refers to a doubly bonded oxygen atomforming carbonyl group with the carbon atom to which the oxygen isattached. Thus, where a ring contains one or more oxo groups, it isintended that that ring contains a carbonyl group in at least one of thering positions.

This invention relates to heterocyclic derivatives that bind to thebenzodiazepine site of GABA_(A) receptors, including human GABA_(A)receptors. A compound may bind to such sites with high affinity but nothigh specificity or a compound may bind with high selectivity but nothigh affinity.

The present invention also encompasses the prodrugs of the compounds ofFormula I. Those skilled in the art will recognize various syntheticmethodologies that may be employed to prepare non-toxic pharmaceuticallyacceptable prodrugs of the compounds encompassed by Formula I. Thoseskilled in the art will recognize a wide variety of non-toxicpharmaceutically acceptable solvates, such as water, ethanol, mineraloil, vegetable oil, and dimethylsulfoxide.

Pharmaceutical Preparations

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preservative agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques. In some cases such coatings may be prepared by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents and flavoring agents may beadded to provide palatable oral preparations. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents orsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical-compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil or amineral oil or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol, glucose or sucrose. Suchformulations may also contain a demulcent, a preservative and flavoringand coloring agents. The pharmaceutical compositions may be in the formof a sterile injectable aqueous or oleaginous suspension. Thissuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents that havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parentallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono-or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It may be convenient toformulate the animal feed and drinking water compositions so that theanimal takes in a therapeutically appropriate quantity of thecomposition along with its diet. It may also be convenient to presentthe composition as a premix for addition to the feed or drinking water.

Representative illustrations of the preparation of compounds of Formula1 in the present invention are given in Schemes 1-3.

In Scheme I, W, X₁, X, and Y are as defined above for Formula 1 and R isC₁-C₆ alkyl, MeOH is methanol, EtOAc is ethyl acetate, DMF isN,N-dimethylformamide, POCl₃ is phosphorus oxychloride, and conc. isconcentrated. Heat, as used herein, means elevated temperature, such as,for example, about 40 to about 250° C.

In Scheme 2, X, X₁, Y, Z, W, W′, J, R₉ and R₁₀ are as defined above forFormula 1, MeOH is methanol, BOP isbenzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate,TEA is triethylamine, DMF is N,N-dimethylformamide, THF istetrahydrofuran. Heat, as used herein, means elevated temperature, suchas, for example, about 40 to about 250° C.

In Scheme 3, X₁, Y, Z, W, X, n, R₁₁ and R₁₂ are as defined above forFormula 1, Me is methyl, Tol is toluene and heat as used herein, meanselevated temperature, such as, for example, about 40 to about 250° C.

Those skilled in the art will recognize that it may be necessary toutilize different solvents or reagents to achieve some of the abovetransformations.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them. Those having skill in the artwill recognize that the starting materials may be varied and additionalsteps employed to produce compounds encompassed by the presentinventions, as demonstrated by the following examples. In some cases,protection of reactive functionalities may be necessary to achieve someof the above transformations. In general, such need for protectinggroups, as well as the conditions necessary to attach and remove suchgroups, will be apparent to those skilled in the art of organicsynthesis.

EXAMPLE 1 Preparation of 1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]piperidine

(1) 4-[(Dimethylamino)methylene]-1H-2-benzopyran-1,3(4H)-dione

100 ml of anhydrous DMF in a 1 liter round-bottomed, three necked flask(fitted with a drying tube containing drierite, and a 125 ml droppingfunnel) is cooled in an ice-salt bath, and 31 ml of POCl₃ issubsequently added over a period of half an hour while stirring the DMF.The 125 ml dropping funnel is replaced with a 150 ml dropping funnel,and a solution of 54 g of homopthalic acid in 100 ml of DMF is added tothe flask over a period of one hour at <10° C. The reaction mixture isthen stirred at room temperature until a yellow paste was formed, andthen poured into ice water. The solid is collected by filtration, washedwith water and dried to give 54 g of the title compound as a yellowsolid, m.p. 137-40° C.

(2) Methyl 1H-2-benzopyran-1-oxo-4-carboxylate

Anhydrous HCl gas is continuously bubbled into a stirred solution of theproduct from part 1 (54 g) in 500 ml of methanol at slowly refluxingtemperature for 6 hours. The reaction mixture is concentrated undervacuum. A NaHCO₃ solution is added to the residue. The solid wascollected by filtration, washed and dried to yield 29.4 g of the titlecompound as a solid, m.p. 88-90° C.

(3) Methyl 1,2-dihydro-1-oxo-4-isoquinolinecarboxylate

A mixture of the product from part 2 (29 g) and ammonium acetate (50 g)in 100 ml of acetic acid is stirred at 80° C. overnight, and then cooledand poured into water. The solid is collected by filtration, washed withwater and dried to yield the title compound (25 g) as a white solid,m.p. 258-60° C.

(4) Methyl 1-chloroisoquinoline-4-carboxylate

A mixture of the product from part 3 (12.5 g) in 50 ml of POCl₃ isstirred at 100° C. for about two hours then cooled and concentratedunder vacuum. The residue is dissolved in 300 ml of CHCl₃, and theresulting solution is washed with aqueous NaHCO₃ and water, dried overNa₂SO₄, filtered and then concentrated to give the title compound, m.p.53-55° C.

(5) Methyl 1-isoquinolinecarbonitrile-4-carboxylate

A mixture of the product from part 4 (16 g) and potassium cyanide (5.4g) in 50 ml of DMF was stirred at 90° C. for 4 hours. The mixture iscooled and poured into water. The solid is then collected by filtration,washed with water, and dried to give the title compound as a tan solid(11 g), m.p. 91-94° C.

(6) Methyl 1-isoquinolinemethanamine-4-carboxylate dihydrochloride

A mixture of the product from part 5 (2 g) and 10% Pd on carbon (800 mg)in 50 ml of methanol containing 4 ml of conc. HCl is hydrogenated with aballoon of hydrogen for about half an hour. The mixture is filteredthrough celite and concentrated under vacuum to a solid.Recrystallization from EtOAc and methanol yields the title compound (1.8g) as a white solid, m.p. 234-237° C. (dec).

(7) N-[(4-methoxycarbonylisoquinolin-1-yl)methyl]benzamide

Benzoyl chloride (0.78 ml) is added dropwise to a stirred mixture of theproduct from part 6 (1.87 g) in 10 ml EtOAc and 10 ml of saturatedaqueous NaHCO₃ solution. After stirring for 15 minutes, the layers areseparated, the organic layer is washed with water, dried, filtered andconcentrated to a solid. The solid is washed with hexanes and dried toyield 1.97 g of the desired product as a white solid, m.p. 140-142° C.

(8) Methyl 3-phenylimidazo[5,1-a]isocuinolin-6-carboxylate

A mixture of the product from part 7 (1.97 g) in 10 ml of POCl₃ isstirred at 105° C. for two hours, then cooled and concentrated undervacuum. The residue is treated with EtOAc and washed with saturatedaqueous NaHCO₃ solution and water. The organic solution is dried overNa₂SO₄, filtered and then concentrated to afford a solid.Recrystallization from 2-propanol yields the title compound as a yellowsolid (0.7 g).

(9) 3-Phenylimidazo[5,1-a]isoquinolin-6-carboxylic acid

A slurry of the product from part 8 (488 mg) and NaOH (226 mg) in 15 mlof methanol and 10 ml of water is stirred at 60° C. until a solutionforms. The methanol is then evaporated in vacuo, and the remainingmixture is diluted with water. After adjusting the pH to 5-6 with 1NHCl, the solid is collected by filtration, washed with water and driedto give the title compound (450 mg) as a yellow solid, m.p. 187-90° C.

(10)1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-piperidine

A mixture of the product from part 9 (95 mg), BOP (220 mg), piperidine(56 mg) and TEA (67 mg) in 2 ml of DMF is stirred at room temperaturefor 18 hours. The mixture is added to aqueous NaHCO₃ solution andextracted with EtOAc. The organic layer is washed with brine and water,dried (Na₂SO₄), filtered and concentrated to afford a foam. Purificationon a silica gel column, eluting with 5% methanol in methylene chloride,gives the title compound. ¹H NMR (CDCl₃) δ 1.38-1.50 and 1.60-1.80 (6H,m), 3.18-3.36 (2H, m), 3.65-3.95 (2H, m), 7.40-7.60 (6H, m), 7.75 (2H,d), 7.95 (1H, s), 8.05 (1H, s), 8.10 (1H, d). The hydrochloride salt wasprepared by treating the free base in EtOAc with a solution of hydrogenchloride in ether and collecting by filtration.

LC-MS data: HPLC: 1.93 min (HPLC method: Zorbax XDB-C₁₈ column, 4.6×30mm, 3.5 μm particle size, 3 min gradient from 0 to 100% B with 0.5 minhold at 100% B. Solvent A: 95% H₂O-5% MeOH-0.05% TFA; Solvent B: 95%MeOH-5% H₂O-0.05% TFA). MS (ES⁺): m/e 356 [M+H]⁺.

EXAMPLES 2-40

The following compounds are prepared using procedures analogous to thoseof Example 1. The compounds of these examples have the general structureshown below:

where Q and W are defined in the following Table 1. LC-MS data are givenas HPLC retention times (rt) and [M+H]⁺. The HPLC retention times ofTable 1 are obtained by the method given in Example 1.

TABLE 1 HPLC Ex. rt No. Q W Compound Name (min) [M + H]⁺ 2

1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-pyrrolidine 1.70342 3

(R)-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-2-hydroxymethyl-pyrrolidine 1.47 372 4

4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-morpholine 1.44 3585

cis-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-2,6-dimethylpiperidine2.27 384 6

4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-thiomorpholine 1.84374 7

1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-4-methylpiperazine0.94 371 8

cis-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-3,5-dimethylpiperazine1.13 385 9

1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-N,N-dimethylamine1.40 316 10

1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-N,N-diethylamine1.80 344 11

1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine1.80 360 12

(R)-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl)-2-hydroxymethyl-pyrrolidine1.63 390 13

1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine2.08 374 14

1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine1.97 360 15

(R)-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine1.73 390 16

1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine2.22 374 17

1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-pyrrolidine1.61 348 18

(R)-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl)-2-hydroxymethyl-pyrrolidine1.40 378 19

1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-piperidine1.89 362 20

4-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-1,1-dioxido-thiomorpholine1.24 406 21

cis-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl)-3,5-dimethyl-piperazine1.22 402 22

cis-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}}-3,5-dimethyl-piperazine1.37 402 23

cis-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-}}-3,5-dimethyl-piperazine1.04 391 24

1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine2.10 376 25

(R)-1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine1.92 406 26

cis-1-{[3-(4-Chlorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3,5-dimethyl-piperazine1.54 419 27

1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinoline-6-yl]carbonyl}-4-methylpiperidine376 28

(R)-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl)-3-methyl-piperazine377 29

(S)-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methyl-piperazine377 30

4-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}morpholine 36431

1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine360 32

cis-1-{[3-(Thien-3-yl)imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2,5-dimethylpiperazine391 33

1-{[3-(4-Methylisoxazol-3-yl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}pyrrolidine347 34

4-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}morpholine376 35

(R)-1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-2-hydroxymethyl-pyrrolidine390 36

1-{[3-(3-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}piperidine374 37

S-1-[(3-Phenylimidazo[5,1-a]isoquinolin-6-yl)carbonyl]-3-methylpiperazine371 38

(S)-1-{[3-(2-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methylpiperazine389 39

(S)-1-{[3-(4-Fluorophenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-3-methylpiperazine389 40

(S)-1-{[3-(4-Methoxyphenyl)-imidazo[5,1-a]isoquinolin-6-yl]carbonyl}-homopiperazine400

EXAMPLE 41 Preparation of1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine

(1) Methyl 3-phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-carboxylate

A mixture of methyl 1-chloroisoquinoline-4-carboxylate, preparedessentially according to procedures described in Example 1, part 4, (293mg) and benzoic hydrazide (192 mg) in 8 ml of DMF is stirred at 100° C.overnight. The mixture is cooled and poured into water. The solid isthen collected by filtration and dried to give the title compound as asolid (258 mg). LC-MS data for the title compound: HPLC: 2.34 min. MS(ES⁺) m/e 304 [M+H]⁺. (The HPLC retention time is obtained by the methodof Example 1).

(2) 3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-carboxylic acid

This compound is prepared using the procedure described in Example 1,part 9 with the product of part 1 of this example being used as thestarting material.

(3)1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine

This compound is prepared essentially using the procedure described inExample 1, part 10 with the product of part 2 of this example being usedas the starting material. Data for the title compound: ¹H NMR (CDCl3) δ1.38-2.00 (6H, m), 3.16-3.36 (2H, m), 3.65-3.95 (2H, m), 7.50-7.86 (8H,m), 8.05 (1H, s), 8.82 (1H, d).

LC-MS data: HPLC: 2.13 min. MS (ES⁺) m/e 357 [M+H]⁺. (The HPLC retentiontime is obtained by the method given in Example 1).

EXAMPLES 42-45

The following compounds are prepared by procedures analogous to those ofExample 41. These compounds are represented by the general structureshown below:

where Q and W are defined in Table 2. HPLC-MS data are given as HPLCretention times (Tr) and [M+H]⁺. The HPLC retention time is obtained bythe method of Example 1.

TABLE 2 HPLC Ex. (Tr) No. Q W Compound Name (min) [M + H]⁺ 42

1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]pyrrolidine1.93 343 43

(R)-1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]-2-hydroxymethyl-pyrrolidine1.73 373 44

4-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]morpholine1.74 359 45

cis-1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]-3,5-dimethylpiperazine1.37 386

EXAMPLE 46 Preparation of3-Phenyl-6-(S-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]imidazole-3-yl-)-imidazo[5,1-a]isoquinoline

A solution of trimethylaluminum in anhydrous toluene (1M, 2.5 ml) isadded dropwise to a stirred solution of S-2-(aminomethyl) pyrrolidine(250 mg) in 10 ml of anhydrous toluene. The mixture is then slowlywarmed to 80° C. and stirred for one hour. After cooling to roomtemperature, methyl 3-phenylimidazo[5,1-a]isoquinolin-6-carboxylate(prepared essentially according to procedures described in Example 1,part 8, 97 mg) was added in one portion. The reaction mixture is heatedat reflux for 12 hours under nitrogen. After cooling, the solution istreated dropwise with 5 ml of water, diluted with 10 ml of methanol and10 ml of methylene chloride, and refluxed for another 15 minutes. Afterfiltration over celite and Na₂SO₄, and solvent evaporation, the residueis mixed with EtOAc and water. The organic layer is then separated,washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The residue is purified on a silica gel column, eluting with 5% methanolin methylene chloride to yield the titled compound. ¹H NMR (CDCl₃) δ1.40-2.05 (4H, m), 3.00-3.20 (2H, m), 3.80-4.20 (3H, m), 7.40-7.62 (5H,m), 7.80 (2H, d), 7.95 (1H, s), 8.08 (1H, d), 8.35 (1H, d), 8.40 (1H,s).

LC-MS data: HPLC: 1.51 min. MS (ES⁺) m/e 353 [M+H]⁺. The HPLC retentiontime was obtained by the method of Example 1.

EXAMPLE 47 Preparation of1-[(3-Phenyl-1,2,4-triazolo[3,4-a]isoquinoline-6-yl)carbonyl]piperidine

(1) 3-phenyl-1,2,4-Triazolo[3,4-a]phthalazine-6-carboxylic acid

A mixture of 6-Chloro-3-phenyl-1,2,4-Triazolo[3,4-a]phthalazine (2.0 g,prepared according to procedures described in Zh. Org. Khim. (1975),11(7), 1570-2 and J. Med. Chem. (1988), 31(6), 1115-23.) and coppercynaide (2.0 g) in 50 ml of DMSO is stirred at 140° C. overnight. Themixture is cooled, poured into water and extracted with methylenechloride. The organic layer is washed with water, dried over Na₂SO₄ andconcentrated to give a tan solid which is then dissolved in 50 mL ofmethanol. The resulting solution is saturated with HCl gas and themixture is stirred at room temperature overnight. 20 mL of water and 1mL of 10 N NaOH solution are added, the resulting mixture is then heatedunder reflux for 4 hours. The methanol is then evaporated in vacuo, andthe remaining mixture is diluted with water. After adjusting the pH to4-5 with 1N HCl, the solid is collected by filtration, and dried to givethe title compound as a solid.

(2) 1-[(3-Phenyl-1,2,4-triazolo[3,4-a]phthalazine-6-yl)carbonyl]piperidine

This compound is prepared essentially using the procedure described inExample 1, part 10 with the product of part 1 of this example being usedas the starting material.

EXAMPLE 48

Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention may be prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). Suchradiolabeled probes are conveniently synthesized by a radioisotopesupplier specializing in custom synthesis of radiolabeled probecompounds. Such suppliers include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Tritium labeled probecompounds can also be prepared, when appropriate, by sodium borotritidereduction. Such preparations are also conveniently carried out as acustom radiolabeling by any of the suppliers listed in the precedingparagraph using the compound of the invention as substrate.

EXAMPLE 49

Receptor Autoradiography

Receptor autoradiography (receptor mapping) is carried out in vitro asdescribed by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols inPharmacology (1998) John Wiley & Sons, New York, using radiolabeledcompounds of the invention prepared as described in the precedingExample.

EXAMPLE 50

Binding Assay

The high affinity and high selectivity of compounds of this inventionfor the benzodiazepine site of the GABA_(A) receptor is demonstratedusing the following binding assay. This assay is carried out essentiallyas described by Thomas and Tallman (J. Bio. Chem. 1981; 156:9838-9842,and J. Neurosci. 1983; 3:433-440).

Rat cortical tissue is dissected and homogenized in 25 volumes (w/v) ofBuffer A (0.05 M Tris HCl buffer, pH 7.4 at 4° C.). The tissuehomogenate is centrifuged in the cold (4° C.) at 20,000×g for 20minutes. The supernatant is decanted, the pellet rehomogenized in thesame volume of buffer, and centrifuged again at 20,000×g. Thesupernatant of this centrifugation step is decanted and the pelletstored at −20° C. overnight. The pellet is then thawed and resuspendedin 25 volumes of Buffer A (original wt/vol), centrifuged at 20,000×g andthe supernatant decanted. This wash step is repeated once. The pellet isfinally resuspended in 50 volumes of Buffer A.

Incubations contained 100 μl of tissue homogenate, 100 μl ofradioligand, (0.5 nM ³H-Ro15-1788 [³H-Flumazenil], specific activity 80Ci/mmol), and test compound or control (see below), and are brought to atotal volume of 500 μl with Buffer A. Incubations are carried for 30 minat 4° C. and then rapidly filtered through Whatman GFB filters toseparate free and bound ligand. Filters are washed twice with freshBuffer A and counted in a liquid scintillation counter. Nonspecificbinding (control) is determined by displacement of ³H Ro15-1788(³H-Flanazenil) with 10 μM Diazepam (Research BiochemicalsInternational, Natick, Mass.). Data are collected in triplicate,averaged, and percent inhibition of total specific binding (TotalSpecific Binding—Total—Nonspecific) is calculated for each compound.

A competition binding curve is obtained with up to 11 points spanningthe compound concentration range from 10⁻¹²M to 10⁻⁵M obtained per curveby the method described above for determining percent inhibition. K_(i)values are calculated according the Cheng-Prussof equation. Each of thecompounds shown and described in Examples 1 through 46, and tested inthis assay was found to have a K_(i) of <1 μM.

EXAMPLE 51

Electrophysiology

The following assay is used to determine if a compound of the inventionact as an agonist, an antagonist, or an inverse agonist at thebenzodiazepine site of the GABA_(A) receptor.

Assays are carried out as described in White and Gurley (NeuroReport 6:1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory(Receptors and Channels 3: 1-5, 1995) with modifications.Electrophysiological recordings are carried out using the two electrodevoltage-clamp technique at a membrane holding potential of −70 mV.Xenopus Laevis oocytes are enzymatically isolated and injected withnon-polyadenylated cRNA mixed in a ratio of 4:1:4 for α, β and γsubunits, respectively. Of the nine combinations of α, β and γ subunitsdescribed in the White et al. publications, preferred combinations areα₁β₂γ₂, α₂β₃γ₂, α₃β₃γ₂, and α₅β₃γ₂. Preferably all of the subunit cRNAsin each combination are human clones or all are rat clones. The sequenceof each of these cloned subunits is available from GENBANK, e.g., humanα₁, GENBANK accession no. X14766, human α₂, GENBANK accession no.A28100; human α₃, GENBANK accession no. A28102; human α₅, GENBANKaccession no. A28104; human β₂, GENBANK accession no. M82919; human α₃,GENBANK accession no. Z20136; human γ₂, GENBANK accession no. X15376;rat α₁, GENBBANK accession no. L08490, rat α₂, GENBANK accession no.L08491; rat α₃, GENBANK accession no. L08492; rat α₅, GENBANK accessionno. L08494; rat β₂. GENBANK accession no. X15467; rat β₃, GENBANKaccession no. X15468; and rat γ₂, GENBANK accession no. L08497. For eachsubunit combination, sufficient message for each constituent subunit isinjected to provide current amplitudes of >10 nA when 1 μM GABA isapplied.

Compounds are evaluated against a GABA concentration that evokes <10% ofthe maximal evokable GABA current (e.g. 1 μM-9 μM). Each oocyte isexposed to increasing concentrations of compound in order to evaluate aconcentration/effect relationship. Compound efficacy is calculated as apercent-change in current amplitude: 100*((Ic/I)−1), where Ic is theGABA evoked current amplitude observed in the presence of test compoundand I is the GABA evoked current amplitude observed in the absence ofthe test compound.

Specificity of a compound for the benzodiazepine site is determinedfollowing completion of a concentration/effect curve. After washing theoocyte sufficiently to remove previously applied compound, the oocyte isexposed to GABA+1 μM RO15-1788, followed by exposure to GABA+1 μMRO15-1788+test compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in thepresence of RO15-1788 is subtracted from the percent changes in currentamplitude observed in the absence of 1 μM RO15-1788. These net valuesare used for the calculation of average efficacy and EC₅₀ values bystandard methods. To evaluate average efficacy and EC₅₀ values, theconcentration/effect data are averaged across cells and fit to thelogistic equation.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein: X represents N;X₁ represents N; each R₂ independently represents hydrogen, halogen,hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, mono or di(C₁-C₆)alkylamino, or amino(C₁-C₆)alkyl; Wis aryl or heteroaryl, each of which is optionally substituted with oneor more groups R_(A), wherein each R_(A) is independently i) halogen,hydroxy, cyano, nitro, amino, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈ alkyl), —N(C₁-C₈alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl) CO₂(C₁-C₈ alkyl), —CONH₂,—CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl),—S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), or —SO₂(C₁-C₈ alkyl); ii) aryl orheteroaryl, each of which is optionally substituted with one or twogroups independently selected from halogen, hydroxy, cyano, nitro,amino, C₁-C₆ alkyl, C₁-C₆alkoxy, trifluoromethyl, trifluoromethoxy, monoor di(C₁-C₆)alkylamino, and amino(C₁-C₆)alkyl; iii) C₁-C₈alkyl,C₂C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈cycloalkyl, C₃C₈cycloalkyl(C₁-C₃alkyl), C₃-C₈cycloalkenyl, each of which is unsubstituted or substitutedby one or more substitutuents independently selected from hydroxy, oxo,halogen, C₁-C₆alkoxy, —CONH₂, —CONHC₁-C₆alkyl,—CON(C₁-C₆alkyl)(C₁-C₆alkyl), —COOH, and —CO₂C₁-C₆alkyl; or iv) NR₄R₅,wherein R₄, R₅ and the nitrogen to which they are attached form amonocyclic or bicyclic ring optionally containing one or more of oxo, O,S, SO, SO₂, or NR₆ wherein R₆ is hydrogen, C₁-C₆alkyl, orAr—(C₁-C₆alkyl) where Ar is aryl or heteroaryl, each of which isoptionally substituted with one or two groups independently selectedfrom halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino, andamino(C₁-C₆)alkyl; and Q is selected Formulas III, IV and V:

wherein: J is N or C₁-C₈ alkylene; and R₉ and R₁₀ are independentlyhydrogen, C₁-C₈ alkyl, or Ar₁, wherein Ar₁ is aryl or heteroaryl, eachof which may be substituted with one or two of R_(B), where each R_(B)independently carries the definition of R_(A); or R₉, R₁₀ and the atomto which they are attached form a 4- to 8-membered monocyclic orbicyclic ring optionally containing one or more double bonds or one ormore of oxo, O, S, SO, SO₂, or N—R₈ wherein R₈ is hydrogen, C₁-C₈ alkyl,or Ar₁—(C₁-C₈ alkyl); wherein Ar₁ is optionally substituted with one ortwo of R_(B), where each R_(B) independently carries the definition ofR_(A); and wherein the monocyclic or bicyclic ring is optionallysubstituted with C₁-C₆ alkyl or hydroxy(C₁-C₆)alkyl; R₁₁ is selectedfrom the group consisting of hydrogen, C₁-C₈ alkyl, C₁-C₈ alkanoyl,aryl(C₁-C₆)alkyl, and aryl (C₁-C₆)alkanoyl; and R₁₂ is selected from thegroup consisting of hydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; or R₁₁ andR₁₂ together with the atoms to which they are attached form a 5-8membered monocyclic ring which is optionally substituted with one ormore of halogen, hydroxy, cyano, nitro, amino, C₁-C₆ alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, mono or di(C₁-C₆)alkylamino, oramino(C₁-C₆)alkyl; and n is 1, 2, 3, or 4; and W′ (i) independentlycarries the same definition as W; (ii) represents —OR where R isaryl(C₁-C₆)alkyl; or (iii) is M₅ where M₅ is C₁-C₈ alkyl,aryl(C₁-C₆)alkyl or —N(C₁-C₄ alkyl)(C₁-C₄ alkoxy).
 2. A compoundaccording to claim 1 of the formula

wherein each R₂, Q, X, and X₁ are defined as in claim 1, and W isphenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,pyrimidyl, imidazolyl, benzoimidazolyl, furanyl, benzofuranyl,thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl,benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl orbenzopyrazolyl, each of which is unsubstituted or substituted with oneor more substituents independently selected from the group consistingof: halogen, hydroxy, cyano, nitro, amino, C₁-C₈alkyl, C₁-C₆alkoxy,trifluoromethyl, trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl),—SO₂N(C₁₋₈ alkyl)(C₁-C₈ alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁₋₈alkyl), —N(C₁-C₈ alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl),—CONH₂, —CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈alkyl), —S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.3. A compound according to claim 2 wherein W is phenyl, naphthyl,thienyl, pyridyl, pyrazinyl, pyrimidyl, imidazolyl, isoxazolyl, furanyl,thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl or benzopyrazolyl, eachof which is unsubstituted or substituted with one or more substituentsindependently selected from the group consisting of: halogen, hydroxy,cyano, nitro, amino, C₁-C₈alkyl, C₁-C₆alkoxy, trifluoromethyl,trifluoromethoxy, —SO₂NH₂, —SO₂NH(C₁-C₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁-C₈alkyl), —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)(C₁-C₈ alkyl), —N(C₁-C₈alkyl)CO(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)CO₂(C₁-C₈ alkyl), —CONH₂,—CONH(C₁-C₈ alkyl), —CON(C₁-C₈ alkyl) (C₁-C₈ alkyl), —CO₂(C₁-C₈ alkyl),—S(C₁-C₈ alkyl), —SO(C₁-C₈ alkyl), —SO₂(C₁-C₈ alkyl) and phenyl.
 4. Acompound according to claim 3, wherein R₂ is independently selected ateach occurrence from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy,halogen, hydroxy, trifluoromethyl and trifluoromethoxy; Q is selectedfrom the group consisting of Formulas III, IV and V:

wherein: J is N or C₁-C₈ alkylene; and R₉ and R₁₀ are independentlyhydrogen, C₁-C₈ alkyl; or R₉, R₁₀ and the atom to which they areattached form a 4- to 8-membered monocyclic or bicyclic ring, which maycontain one or more double bonds or one or more of oxo, O, S, SO, SO₂,or N—R₈ wherein R₈ is hydrogen, C₁-C₈ alkyl; wherein the monocyclic orbicyclic ring is optionally substituted with C₁-C₆ alkyl orhydroxy(C₁-C₆)alkyl; R₁₁ is selected from the group consisting ofhydrogen, C₁-C₈ alkyl, C₁-C₈ alkanoyl, aryl(C₁-C₆)alkyl, andaryl(C₁-C₆)alkanoyl; and R₁₂ is selected from the group consisting ofhydrogen, C₁-C₈ alkyl, and C₁-C₈ alkoxy; or R₁₁ and R₁₂ together withthe atoms to which they are attached form a 5-8 membered monocyclicring, which is optionally substituted with C₁-C₆ alkyl; and n is 1, 2,3, or 4; W′ phenyl, pyridyl, or naphthyl; and W is phenyl, thienyl,isoxazolyl, or pyridyl, each of which is unsubstituted or substitutedwith one or more substituents independently selected from the groupconsisting of halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, trifluoromethyl,trifluoromethoxy, and hydroxy.
 5. A compound according to claim 1,wherein Q is —C(O)M₅.
 6. A pharmaceutical composition comprising acompound according to claim 1 combined with at least onepharmaceutically acceptable carrier or excipient.
 7. A method for thetreatment of a disease or disorder selected from the group consisting ofdepression, anxiety, and attention deficit disorder said methodcomprising administering to a patient in need of such treatment orprevention an effective amount of a compound of claim
 1. 8. A compoundaccording to claim 1, which is:1-[(3-Phenyl-1,2,4-triazolo[3,4-a]phthalazines-6-yl)carbonyl]piperidine, or a pharmaceutically acceptable salt thereof.